β-石竹烯通过抑制Keap1/Nrf2/ARE途径介导的铁死亡在减轻糖尿病视网膜病变大鼠病理损伤中的作用OA

Objective To investigate the effect of β-caryophyllene(BCP)in alleviating the pathological damage of diabetic retinopathy(DR)in rats by inhibiting ferroptosis mediated by the Kelch-like ECH-associated protein 1(Keap1)/nuclear factor erythroid 2-related factor 2(Nrf2)/antioxidant response element(ARE)pathway.Methods Rats were di-vided into the NC group,DR group,50-BCP group,100-BCP group,200-BCP group,and 200-BCP+Nrf2 inhibitor(Nrf2-IN-1)group(n=12 per group).The NC group served as the control,and the other groups were established as DR models induced by streptozotocin(STZ).Rats in the NC group and DR group were given 5 g·L-1 sodium carboxymethylcellulose(CMC-Na)by gavage.Rats in the 50-BCP group,100-BCP group,and 200-BCP group were intragastrically administered 50,100,and 200 mg·kg-1BCP,respectively.Rats in the 200-BCP+Nrf2-IN-1 group were simultaneously given 200 mg·kg-1 BCP and 1 mg·kg-1Nrf2-IN-1 by gavage.After 4 weeks of treatment,fasting blood glucose(FBG)was detected by a blood glucose meter,and glycated hemoglobin(HbA1c)was measured using the enzyme-linked immunosorbent assay.Retinal morphology was observed by hematoxylin-eosin staining.The levels of malondialdehyde(MDA),reduced glutathione(GSH),and Fe2+in the retina were determined by microassay.Quantitative real-time polymerase chain reaction was used to detect the rela-tive mRNA expression levels of ferritin heavy chain 1(FTH1),ferroportin 1(FPN1),transferrin receptor(TFRC),and glu-tathione peroxidase 4(GPX4)in the retina.Western blot was performed to measure the protein expression levels of GPX4,Keap1,and nuclear Nrf2 in the retina.Results Compared with the DR group,the 50-BCP,100-BCP,200-BCP,and 200-BCP+Nrf2-IN-1 groups showed decreased FBG and HbA1 c,improved retinal morphology,reduced MDA content,increased GSH content,decreased retinal Fe2+content,upregulated relative mRNA expression levels of retinal FTH1 and FPN1,elevated mRNA and protein expression levels of GPX4,downregulated TFRC mRNA expression,decreased retinal Keap1 protein ex-pression,and increased nuclear Nrf2 protein expression(all P＜0.05).Compared with the 200-BCP group,the 200-BCP+Nrf2-IN-1 group exhibited increased FBG and HbA1 c,deteriorated retinal morphology,increased MDA content,decreased GSH content,elevated retinal Fe2+content,downregulated relative mRNA expression levels of retinal FTH1 and FPN1,re-duced relative mRNA and protein expression levels of GPX4,upregulated TFRC mRNA expression,increased retinal Keap1 protein expression,and decreased nuclear Nrf2 protein expression(all P＜0.05).Conclusion BCP alleviates the patho-logical damage of DR in rats by inhibiting ferroptosis mediated by the Keap1/Nrf2/ARE pathway.